Tumor-derived DNA can be found in the plasma of cancer patients. In this study, we explored the use of shotgun massively parallel sequencing (MPS) of plasma DNA from cancer patients to scan a cancer ...genome noninvasively.
Four hepatocellular carcinoma patients and a patient with synchronous breast and ovarian cancers were recruited. DNA was extracted from the tumor tissues, and the preoperative and postoperative plasma samples of these patients were analyzed with shotgun MPS.
We achieved the genomewide profiling of copy number aberrations and point mutations in the plasma of the cancer patients. By detecting and quantifying the genomewide aggregated allelic loss and point mutations, we determined the fractional concentrations of tumor-derived DNA in plasma and correlated these values with tumor size and surgical treatment. We also demonstrated the potential utility of this approach for the analysis of complex oncologic scenarios by studying the patient with 2 synchronous cancers. Through the use of multiregional sequencing of tumoral tissues and shotgun sequencing of plasma DNA, we have shown that plasma DNA sequencing is a valuable approach for studying tumoral heterogeneity.
Shotgun DNA sequencing of plasma is a potentially powerful tool for cancer detection, monitoring, and research.
The dynamic properties of mitochondria-including their fusion, fission, and degradation-are critical for their optimal function in energy generation. The interplay of fusion and fission confers ...widespread benefits on mitochondria, including efficient transport, increased homogenization of the mitochondrial population, and efficient oxidative phosphorylation. These benefits arise through control of morphology, content exchange, equitable inheritance of mitochondria, maintenance of high-quality mitochondrial DNA, and segregation of damaged mitochondria for degradation. The key components of the machinery mediating mitochondrial fusion and fission belong to the dynamin family of GTPases that utilize GTP hydrolysis to drive mechanical work on biological membranes. Defects in this machinery cause a range of diseases that especially affect the nervous system. In addition, several common diseases, including neurodegenerative diseases and cancer, strongly affect mitochondrial dynamics.
Quantitative measurement of plasma Epstein–Barr virus (EBV) DNA by real-time PCR at the end of primary treatment is a robust prognostic marker for nasopharyngeal carcinoma (NPC) patients. However, up ...to 40% of patients who would later develop disease recurrence had undetectable post-treatment plasma EBV DNA. Targeted sequencing for the entire EBV genome potentially allows a more comprehensive and unbiased detection of plasma EBV DNA and enables the use of other parameters such as fragment size as biomarkers. Hence, we explored if plasma EBV DNA sequencing might allow more accurate prognostication of NPC patients.
Plasma samples collected from 769 patients with stage IIB-IVB NPC at 6-8 weeks after radiotherapy were analysed using targeted sequencing for EBV DNA.
The sensitivities of the PCR-based analysis, at a cut-off of any detectable levels of plasma EBV DNA, for prediction of local and distant recurrences were 42.3% and 85.3%, respectively. The sequencing-based analysis (involving quantitation and size profiling) achieved better performance for both local and distant recurrences than PCR. Using a cut-off of the proportion of plasma EBV DNA deduced by sequencing at 0.01%, the sensitivities of the sequencing-based analysis for local and distant recurrences were 88.5% and 97.1%, with the resultant negative predictive values of 99.1% and 99.4%, respectively. Among patients with undetectable EBV DNA on quantitative PCR, sequencing could further define a subgroup that enjoyed superior survival outcomes based on the proportion of plasma EBV DNA, with a 5-year progression-free survival (PFS) approaching 90%. On multivariate analysis, sequencing-based quantitative level of plasma EBV DNA was the independent prognostic factor with the highest hazard ratio for prediction of overall survival and PFS.
NPC prognostication using post-treatment plasma EBV DNA could be enhanced through sequencing.
•PCR-based analysis of plasma EBV DNA has limited sensitivity in predicting recurrences of NPC.•Sequencing analysis of post-treatment plasma EBV DNA improves the sensitivity for both local and distant relapses of NPC.•Sequencing analysis of post-treatment plasma EBV DNA could better stratify the mortality risk of NPC patients than PCR.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
With the more stringent regulations on emissions and fuel economy, global warming, and constraints on energy resources, the electric, hybrid, and fuel cell vehicles have attracted more and more ...attention by automakers, governments, and customers. Research and development efforts have been focused on developing novel concepts, low-cost systems, and reliable hybrid electric powertrain. This paper reviews the state of the art of electric, hybrid, and fuel cell vehicles. The topologies for each category and the enabling technologies are discussed
We explored the detection of genome-wide hypomethylation in plasma using shotgun massively parallel bisulfite sequencing as a marker for cancer. Tumor-associated copy number aberrations (CNAs) could ...also be observed from the bisulfite DNA sequencing data. Hypomethylation and CNAs were detected in the plasma DNA of patients with hepatocellular carcinoma, breast cancer, lung cancer, nasopharyngeal cancer, smooth muscle sarcoma, and neuroendocrine tumor. For the detection of nonmetastatic cancer cases, plasma hypomethylation gave a sensitivity and specificity of 74% and 94%, respectively, when a mean of 93 million reads per case were obtained. Reducing the sequencing depth to 10 million reads per case was found to have no adverse effect on the sensitivity and specificity for cancer detection, giving respective figures of 68% and 94%. This characteristic thus indicates that analysis of plasma hypomethylation by this sequencing-based method may be a relatively cost-effective approach for cancer detection. We also demonstrated that plasma hypomethylation had utility for monitoring hepatocellular carcinoma patients following tumor resection and for detecting residual disease. Plasma hypomethylation can be combined with plasma CNA analysis for further enhancement of the detection sensitivity or specificity using different diagnostic algorithms. Using the detection of at least one type of aberration to define an abnormality, a sensitivity of 87% could be achieved with a specificity of 88%. These developments have thus expanded the applications of plasma DNA analysis for cancer detection and monitoring.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Circulating Epstein–Barr virus DNA was measured in 20,174 asymptomatic participants in Hong Kong; 34 of 309 with positive results had nasopharyngeal cancer. Stage distribution and progression-free ...survival were better in the 34 participants than in a historical cohort.
Mitochondria are dynamic organelles that continually undergo fusion and fission. These opposing processes work in concert to maintain the shape, size, and number of mitochondria and their ...physiological function. Some of the major molecules mediating mitochondrial fusion and fission in mammals have been discovered, but the underlying molecular mechanisms are only partially unraveled. In particular, the cast of characters involved in mitochondrial fission needs to be clarified. By enabling content mixing between mitochondria, fusion and fission serve to maintain a homogeneous and healthy mitochondrial population. Mitochondrial dynamics has been linked to multiple mitochondrial functions, including mitochondrial DNA stability, respiratory capacity, apoptosis, response to cellular stress, and mitophagy. Because of these important functions, mitochondrial fusion and fission are essential in mammals, and even mild defects in mitochondrial dynamics are associated with disease. A better understanding of these processes likely will ultimately lead to improvements in human health.
Mitochondria are renowned for their central bioenergetic role in eukaryotic cells, where they act as powerhouses to generate adenosine triphosphate from oxidation of nutrients. At the same time, ...these organelles are highly dynamic and undergo fusion, fission, transport, and degradation. Each of these dynamic processes is critical for maintaining a healthy mitochondrial population. Given the central metabolic function of mitochondria, it is not surprising that mitochondrial dynamics and bioenergetics reciprocally influence each other. We review the dynamic properties of mitochondria, with an emphasis on how these processes respond to cellular signaling events and how they affect metabolism.
Cancer and stem cells appear to share a common metabolic profile that is characterized by high utilization of glucose through aerobic glycolysis. In the presence of sufficient nutrients, this ...metabolic strategy provides sufficient cellular ATP while additionally providing important metabolites necessary for the biosynthetic demands of continuous cell proliferation. Recent studies indicate that this metabolic profile is dependent on genes that regulate the fusion and fission of mitochondria. High levels of mitochondrial fission activity are associated with high proliferation and invasiveness in some cancer cells and with self-renewal and resistance to differentiation in some stem cells. These observations reveal new ways in which mitochondria regulate cell physiology, through their effects on metabolism and cell signaling.
Cancer and stem cells often have similar metabolic profiles characterized by high utilization of glucose to support cell growth and renewal. Chen and Chan discuss studies showing that this metabolic profile is tailored to the special features of these cells and depends on mitochondrial fusion and fission.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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